Process for the preparation of drug linker compounds
A technology of compounds and derivatives, applied in the field of preparation of drug linker compounds, which can solve problems such as difficult removal of impurities in linker compounds
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
Embodiment 1
[0294] Embodiment 1: the synthesis of Fmoc-Val-OSu
[0295] Fmoc-Val-OSu is commercially available or can be prepared according to the following procedure.
[0296] Fmoc-Val-OH (1.0 eq), N-hydroxysuccinimide (1.3 eq) were dissolved in a mixture of DCM (6 vol) and THF (2 vol). Separately, EDC.HCl (1.2 eq) was dissolved in DCM (10 vol), and the solution was cooled to 0 to 5°C. The Fmoc-Val-OSu / NHS solution was then added to the EDC solution, and the reaction mixture was then warmed to 20 to 25 °C. The reaction mixture was stirred at 20 to 25 °C until the reaction was complete. The reaction mixture was then concentrated under reduced pressure at 40 to 60 °C and azeotropically distilled twice with THF. The concentrated residue was dissolved in THF and filtered to remove EDU. The filtrate was concentrated under reduced pressure at 40 to 60°C and reslurried with n-heptane at 5 to 10°C for 12 hours. The solid was filtered, washed and dried in vacuo (96% yield). MS: m / e 437(MH) ...
Embodiment 2
[0297] The synthesis of embodiment 2.Fmoc-Val-Cit
[0298] Fmoc-Val-OSu (1 eq) was dissolved in acetonitrile (5 vol) at 20°C. Separately, sodium carbonate (1.1 eq) was dissolved in water (5 vol) at 20°C, followed by the addition of L-citrulline (1.1 eq) to obtain a homogeneous clear solution. Water (0.5 vol) was added to the Fmoc-Val-OSu solution and the reaction mixture was heated to 35°C, then the prepared citrulline solution was added dropwise over 10 minutes. The reaction mixture was stirred at 35°C for 3 to 4 hours until the reaction was complete, then cooled to 20°C. Acetonitrile (20 vol) was then added at 20°C over 2 to 3 hours. The resulting suspension is stirred for 1 to 3 hours, then cooled to 0 to 5° C. within 1 to 4 hours and stirred at this temperature for 2 to 3 hours. The solid was filtered, washed and dried under vacuum, then redissolved in N,N-dimethylformamide (3.9 vol), 35.9 g / L aqueous NaCl (3.9 vol), 10% isopropyl A mixture of alcohol in ethyl acetate ...
Embodiment 3
[0299] Synthesis of embodiment 3.Fmoc-Val-Cit-PABOH
[0300]Fmoc-Val-Cit (1 eq), HATU (1.4 eq) were dissolved in a mixture of anhydrous N,N-dimethylformamide (9.5 vol) and ethyl acetate (5 vol) at 20°C. The reaction mixture was then cooled to 0 to 5°C. Separately, a solution of 4-aminobenzyl alcohol (1.5 equiv) in ethyl acetate (2 volumes) and anhydrous N,N-dimethylformamide (0.5 volumes) was prepared. A solution of N,N-diisopropylethylamine (1.4 eq) in ethyl acetate (2 vol) was also prepared. Water (1 volume) was added to the cooled Fmoc-Val-Cit / HATU solution, followed by the rapid addition of the 4-aminobenzyl alcohol solution. Immediately thereafter, the DIPEA solution was added within 25 to 35 minutes. The reaction mixture was stirred at 0 to 5°C for 1 to 2 hours until the reaction was complete. Pre-cooled methyl tert-butyl ether (20 vol) was then added over 10 minutes and the resulting mixture was stirred for 1 to 3 hours. The solid was filtered, washed and dried in ...
PUM
Login to View More Abstract
Description
Claims
Application Information
Login to View More